Studies have shown that glaucoma is the second leading cause of blindness in the United States [Leske M C. The epidemiology of open-angle glaucoma: a review. Am J Epidemiology 1983; 118: 166-191]. The pathologic correlate of glaucoma is the progressive degeneration of retinal ganglion cells and their axons which form the optic nerve.
The classification of glaucoma includes the following different types: Primary angle-closure glaucoma, secondary open-angle glaucoma, steroid-induced glaucoma, traumatic glaucoma, pigmentary dispersion syndrome, pseudoexfoliation syndrome, secondary angle-closure glaucoma, neovascular glaucoma, uveitis and glaucoma and other non further specified eye pathologies. In addition, age-related macular degeneration is a condition which reflects features of glaucoma and leads to a progressive loss of vision, leading finally to blindness.
In the past, the definition of glaucoma included an elevation in the intraocular pressure (IOP) over a normal range. However, many individuals with clearly elevated IOP do not develop glaucoma, and up to 50% of patients with glaucoma do not have an increased IOP.
Currently available medications for the treatment of glaucoma belong to several pharmacological classes, including β-adrenergic blockers, cholinergic agonists, carbonic anhydrase inhibitors, alpha agonists. All operate under a mechanism whereby the IOP is lowered. These existing therapies are typically administered as eye drops. Hyperosmotics may be administered intravenously for emergency treatment. In addition, laser therapy and surgical approaches are applied in special cases.
Irrespective of therapy, after 20 years of follow-up in glaucoma patients, glaucoma-related blindness will have reached 27% in at least one eye and 9% in both eyes [Hattenhauer M G, Johnson D H, Ing H H, et al. The probability of blindness from open-angle glaucoma. Ophthalmology 1998; 105: 2099-2104]. Thus, there exists a significant unmet medical need for alternative treatment strategies. Particularly for patients with progressive glaucomatous damage under normalized IOP, a therapy focusing on the rescue of degenerating retinal ganglion cells is needed.
There are different theories regarding the cause for the degeneration of the retinal ganglion cells including mechanical, vascular and excitotoxic mechanisms. Only recently, β-amyloid (Aβ) has been found to co-localize with dying retinal ganglion cells [McKinnon SJ. Glaucoma: Ocular Alzheimer's disease? Front Biosci. 2003; 8: 1140-1156; Yoneda S, Hara H, Hirata A, Fukushima M, Inomata Y, Tanihara H. Vitreous fluid levels of beta-amyloid ((1-42)) and tau in patients with retinal diseases. Jpn J Ophthalmol. 2005; 49(2): 106-108]. Animal studies demonstrate that, particularly, the soluble Aβ1-42 peptide oligomers are very potent toxins for retinal ganglion cells [Dahlgren K N, Manelli A M, Stine W B Jr, Baker L K, Krafft G A, LaDu MJ. Oligomeric and fibrillar species of amyloid-beta peptides differentially affect neuronal viability. J Biol Chem. 2002; 277(35): 32046-32053uo L, Salt T E, Luong V, Wood N, Cheung W, Maass A, Ferrari G, Russo-Marie F, Sillito A M, Cheetham M E, Moss S E, Fitzke F W, Cordeiro F. Targeting amyloid-β in glaucoma treatment. PNAS 2007; 104 (33): 13444-13449].
The recently published study of Guo, et al. (2007) demonstrated that inhibition of Aβ aggregation reduces glaucomatous degeneration of retinal ganglion cells. The inhibitors used in these animal experiments were Congo red and Aβ antibodies. These agents are pharmacological research tools only and are not appropriate for treatment of humans for various reasons.
Congo red (sodium salt of benzidinediazo-bis-1-naphtylamine-4-sulfonic acid) is a diazo dye. Its original use in the textile industries has long been abandoned because of its toxicity. Congo red binds with moderate specificity to amyloid fibres and is used for histopathological staining. Due to its toxicity, the substance cannot be administered systemically in humans. For the animal experiments, the dye was injected directly into the eyes. The intense color of the solution is, besides the burden of the procedure, prohibitive for an intraocular route of application in humans. As a consequence, Congo red preparations cannot be provided as medication for treatment of glaucoma in humans.
Aβ antibodies are known to block Aβ aggregation relatively specifically [Bard F, Cannon C, Barbour R, Burke R L, Games D, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Lieberburg I, Motter R, Nguyen M, Soriano F, Vasquez N, Weiss K, Welch B, Seubert P, Schenk D, Yednock T. Peripherally administered antibodies against amyloid beta-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer's disease. Nat Med. 2000; 6(8): 916-919]. However, the usefulness of anti-Aβ antibodies for the treatment of glaucoma in humans is limited by the known side effect of these biologicals to induce neutralizing antibodies which leads to a loss of efficacy after repeated administrations. Additional side effects are the provocation of immunogenic inflammatory reactions and the occurrence of antibody-induced microhemorrhages in the target organ [Vasilevko V, Cribbs D H. Novel approaches for immunotherapeutic intervention in Alzheimer's disease. Neurochem Int. 2006; 49(2): 113-126]. Moreover, antibodies are not orally available, which calls for (repeated) injections (frequently leading to skin irritations). Finally, antibody production at an industrial level is rather complicated and expensive.
Theoretically, β-secretase inhibitors could also have beneficial effects on Aβ-related neurotoxicity. However, the observed effects in rat retinal ganglion cells were not significant and this approach does not seem promising for further development in glaucoma [Guo et al. 2007].
It would be an advantage to provide novel methods for the prevention and treatment of ocular disorders, in particular glaucoma, and pharmaceutical compositions for effecting such prevention and treatment thereof. Additional needs in the art which are addressed by the invention will become apparent hereinafter, and still further needs will be apparent to one skilled in the art.